Microparticles and polymers for the mucosal delivery of vaccines
Introduction
The oral route of delivery is the most attractive and acceptable, but is also the most challenging and difficult to exploit for proteins, peptides and other high-molecular-mass molecules. Nevertheless, a live attenuated oral polio vaccine has been successfully marketed for many years and has been used to safely immunize millions of children. Moreover, several additional live attenuated oral vaccines are in late stages of development, including vaccines against rotavirus, Vibrio cholerae and Salmonella typhi. However, many important pathogens cannot be successfully attenuated to allow the development of live mucosally administered vaccines. Moreover, many organisms are difficult or impossible to grow in culture and some cannot be easily manipulated using existing techniques in molecular biology. In addition, it is not yet clear if the available live vectors for mucosal delivery (e.g., Salmonella spp. or polio viruses) can be successfully engineered to express antigens from alternative pathogens. Consequently, there is considerable interest in the development of novel delivery systems for oral administration of vaccines, which can be used to package and deliver a range of antigens from important pathogens. Mainly for reasons of safety, it would be desirable if these novel delivery systems were based on non-living carrier systems, rather than modified bacterial or viral vectors.
Mucosal administration of vaccines offers a number of advantages over the traditional approach to vaccine delivery, which normally involves systemic injection using a needle and syringe. Mucosal delivery of vaccines would avoid the pain and discomfort associated with injections, and would also eliminate the possibility of infections caused by inadequately sterilized needles, or needle re-use. Moreover, mucosal vaccines would be less expensive to produce, since they would not need to be manufactured under such stringent conditions as systemic vaccines. In addition, mucosal vaccines would be less expensive to administer, since trained personnel would not necessarily be required for immunization. Mucosal administration of vaccines might also result in improvements in vaccine efficacy, since mucosal delivery would stimulate mucosal immunity at the sites where most pathogens initially infect hosts. In contrast, systemic immunization does not normally result in the induction of mucosal immunity. The induction of mucosal immunity might prove to be particularly advantageous in the elderly, since unlike systemic immunity, mucosal immunity does not appear to be subject to age-associated dysfunction. Mucosal immunization might also be an attractive approach in the very young, since mucosal immunity appears to develop earlier than systemic immunity. In addition to oral delivery, intranasal immunization is also attractive, since the nose is readily accessible and does not present the problems of low pH and abundant luminal enzymes which are inherent for the oral route. Alternative routes of mucosal immunization which are less attractive, but might be successfully exploited in certain circumstances, include pulmonary inhalation, rectal and ocular immunization.
The use of polymeric microparticles offers significant potential for the development of orally administered vaccines. Microparticles can be prepared from a range of different polymers which can be designed to protect entrapped vaccines against degradation in the gut, to delay the gastric transit of the vaccine or to target vaccines for uptake into the mucosal associated lymphoid tissues (MALTs) of the Peyer's patches (PPs). In addition, similar microparticles can be applied intranasally for the delivery of antigens to the MALTs of the upper respiratory tract. For uptake into the MALT of the gut or the respiratory tract, microparticles need to be prepared with the appropriate dimensions (i.e., <10 μm). As an alternative approach to oral delivery, microparticles may also be designed simply to protect the vaccine against degradation in the gut and to release it in the vicinity of the PPs for subsequent uptake. For this approach, the formulations are usually prepared with much larger dimensions than the microparticles designed for uptake into the MALTs (usually >300 μm). The term “microparticles” will be used in this review to describe a range of polymeric particulate delivery systems, although the real dimensions and characteristics of the delivery systems will be reported whenever possible.
Section snippets
The intestinal uptake of microparticles
A number of researchers have repeatedly demonstrated the uptake of microparticles across the gut following oral administration 1, 2. However, the reported sites of uptake and the mechanisms involved have differed. Overall, four alternative sites and mechanisms of uptake have been emphasized; the villus tips, intestinal macrophages, ordinary enterocytes and the epithelium of the Peyer's patches. It is possible that all of these mechanisms may be operating simultaneously to some extent.
The
Microparticles for oral delivery of drugs
On a number of occasions, particulate delivery systems have been used to enhance the bioavailability of drugs which are normally poorly absorbed following oral administration [24]. Table 2 lists some of the microparticles used as drug delivery systems. Maincent et al. [25]enhanced the oral bioavailability of vincamine in rabbits by adsorption to cyanoacrylate nanoparticles (230 nm). In addition, cyanoacrylate nanoparticles (300 nm) have also been used to enhance the oral absorption of insulin
Microparticles for oral delivery of vaccines
The ability of polymeric microparticles to induce enhanced antibody responses to associated antigens following systemic administration has been known for some time [34]. It is also well established that particulate antigens are more effective for oral immunization than soluble antigens 35, 36. The ability of particulate antigens to induce enhanced immune responses following oral immunization is mainly a consequence of their greater uptake into intestinal Peyer's patches [8]. In the early 1980s,
Enteric-coating of vaccines
Several alternative approaches to the oral administration of vaccines using polymeric delivery systems other than PLGs have also been described, and these approaches have previously been reviewed [24]. One approach involves the use of enteric coating polymers, which are designed to protect the vaccine against low pH in the stomach and to release it in the intestine. Klipstein et al. [88]described the encapsulation of the B subunit of heat-labile enterotoxin (LTB) in an enteric coated
Alternative approaches to oral immunization with polymeric delivery systems
Several additional approaches to the oral delivery of vaccines have been described, which involve the encapsulation or entrapment of vaccine antigens in protective polymer coatings. A novel approach to oral immunization in ruminants was described by Bowerstock et al. [65]. Culture supernatants of Pasteurella haemolytica, a pulmonary pathogen in bovines, was absorbed into poly(methacrylic acid) hydrogels and orally administered to calves. Each of the calves were administered 300 hydrogels per
Conclusions
Mucosal delivery of vaccines, particularly involving the oral route, offers a number of significant advantages over systemic delivery. Most notably, mucosal delivery involves easy administration and improved safety. In addition, unlike systemic immunization, mucosal delivery results in the induction of the secretory immune response, through secretory IgA. There are many alternative approaches to the mucosal delivery of vaccines, involving a range of different delivery systems or vectors 102, 103
Acknowledgements
I would like to acknowledge the contributions made by my various collaborators and colleagues to my own publications included in this review.
References (105)
Intestinal translocation of particulates – implications for drug and antigen delivery
Adv. Drug Deliv. Rev.
(1990)Persorption of starch: physiology and pharmacology
Adv. Pharmacol. Chem.
(1977)- et al.
A study of particulate intestinal absorption and hepatocellular uptake
Exp. Cell Res.
(1961) - et al.
Further histological evidence of the gastrointestinal absorption of polystyrene nanospheres in the rat
Int. J. Pharm.
(1992) - et al.
Controlled release in the gut associated lymphoid tissues. I. Orally administered biodegradable microspheres target the Peyer's patches
J. Control. Release
(1990) - et al.
Microparticulate absorption from the rat intestine
J. Control. Release
(1994) - et al.
Fate of poly(dl-lactide-co-glycolide) nanoparticles after intravenous and oral administration to mice
Int. J. Pharm.
(1994) - et al.
Nanoparticles as carriers for oral peptide absorption: studies on particle uptake and fate
J. Control. Release
(1995) - et al.
Disposition kinetics of vincamine loaded polyalkyl cyanoacrylate nanoparticles
J. Pharm. Sci.
(1986) - et al.
Co-polymerized peptide particles. II. Oral uptake of a novel co-polymeric LHRH nanoparticulate delivery system
J. Control. Release
(1996)
Light microscopical observations on luminally administered dyes, dextrans, nanospheres and microspheres in the pre-epithelial mucus gel layer of the rat distal colon
J. Control. Release
Microparticles as potentially orally active immunological adjuvants
Vaccine
Poly(butyl-2-cyanoacrylate) particles as adjuvants for oral immunization
Vaccine
Poly(lactide-coglycolide) microparticles for the development of single dose controlled release vaccines
Adv. Drug Deliv. Rev.
Biodegradable microparticles as oral vaccines
Vaccine
Controlled release microparticles for oral immunization
Int. J. Pharm.
Salivary, gut, vaginal and nasal antibody responses after oral immunisation with biodegradable microparticles
Vaccine
Size effect on systemic and mucosal immune responses induced by oral administration of biodegradable microspheres
Vaccine
Cholera toxin B subunit (CTB) entrapped in microparticles shows comparable immunogenicity to CTB mixed with whole cholera toxin following oral immunization
Int. J. Pharm.
Poly(dl-lactide-co-glycolide) encapsulated plasmid DNA elicits systemic and mucosal antibody responses to encoded protein after oral administration
Vaccine
Immune responses and protection against Bordetella pertussis infection after intranasal immunization of mice with filamentous haemagglutinin
Vaccine
Intranasal stimulation of long-lasting immunity against aerosol ricin challenge with ricin toxoid vaccine encapsulated in polymeric microspheres
Vaccine
Protective effects of an oral microencapsulated Mycoplasma hyopneumoniae vaccine against experimental infection in pigs
Res. Vet. Sci.
Immunization with a soluble recombinant HIV protein entrapped in biodegradable microparticles induces HIV-specific CD8+ cytotoxic T lymphocytes and CD4+ Th1 cells
Vaccine
Aerosolized suspensions of poly(l-lactic acid) microspheres
Int. J. Pharm.
Mucosal IgA response to rectally administered antigen formulated in IgA-coated liposomes
Vaccine
Specific immune responses in humans following rectal delivery of live typhoid vaccine
Vaccine
Intravaginal immunization in sheep using a bioadhesive microsphere antigen delivery system
Vaccine
Preparation and characterization of a biodegradable microparticle antigen cytokine delivery system
Vaccine
Activation patterns of murine B cells after oral administration of an encapsulated soluble antigen
Vaccine
Immunologic effects of encapsulated short ragweed extract: a potent new agent for oral immunotherapy
Ann. Allergy Asthma Immunol.
Enhancement of rotavirus immunogenicity by microencapsulation
Virology
Comparative analysis of oral delivery systems for live rotavirus vaccines
J. Control. Release
The intestinal uptake of particles and the implications for drug and antigen delivery
J. Anat.
Evidence for the phagocytic transport of intestinal particles in dogs and rats
Infect. Immun.
Comparative, quantitative study of lymphoid and non-lymphoid uptake of 60-nm polystyrene particles
J. Drug Target.
Gastrointestinal uptake of biodegradable microparticles: effect of particle size
Pharm. Res.
Intestinal barrier to large particulates in mice
J. Toxicol. Environ. Health
A method for quantifying particle absorption from the small intestine
Pharm. Res.
The transfer of polystyrene microspheres from the gastrointestinal tract to the circulation after oral administration in the rat
J. Pharm. Pharmacol.
Uptake and tanslocation of fluorescent latex particles by rabbit Peyer's patch follicle epithelium: a quantitative model for M cell uptake
Clin. Exp. Immunol.
Intestinal uptake of fluorescent microspheres in young and aged mice
Proc. Soc. Exp. Biol. Med.
Effect of animal age on the uptake of large particulates across the epithelium of the rat small intestine
Int. J. Exp. Pathol.
Monoclonal antibody directed targeting of fluorescent microspheres to Peyer's patches M cells
Immunology
Confocal analysis of fluorescent bead uptake by mouse Peyer's patch follicle associated M cells
Exp. Physiol.
Incorporation of the reovirus M cell attachment protein into small unilamellar vesicles: incorporation efficiency and binding capability to L929 cells in vitro
J. Microencap.
The oral absorption of micro- and nanoparticulates: neither exceptional nor unusual
Pharm. Res.
New approach for oral administration of insulin with polyalkylcyanoacrylate nanocapsules as drug carrier
Diabetes
Cited by (137)
Microparticles by microfluidic lithography
2023, Materials TodayTowards novel nano-based vaccine platforms for SARS-CoV-2 and its variants of concern: Advances, challenges and limitations
2022, Journal of Drug Delivery Science and TechnologyMicroparticles for Vaccine Delivery
2017, Micro- and Nanotechnology in Vaccine DevelopmentEvaluation of microparticulate ovarian cancer vaccine via transdermal route of delivery
2016, Journal of Controlled ReleaseCitation Excerpt :In addition, the microparticulate delivery system has several advantages over the usage of the antigens alone. Particulate antigens have been proven to be more immunogenic than soluble antigens [13,14]. Improved uptake of the particles compared to the solution results in higher cytotoxic T-lymphocytes (CTLs) response against the cancer cells.
Trends in Nonparenteral Delivery of Biologics, Vaccines and Cancer Therapies
2015, Novel Approaches and Strategies for Biologics, Vaccines and Cancer TherapiesStarch granules as a vehicle for the oral administration of immobilized antigens
2014, Carbohydrate PolymersCitation Excerpt :This induction could indicate that the proteins were properly stabilized and able to reach the sites of immune response induction, located in the gut associated lymphoid tissue (GALT). Microparticulated systems for antigen delivery enhanced both the antigen's stability in the gastrointestinal tract and the capture of the desired proteins or peptides (O’Hagan, 1998). Frequently, these systems use chemical cross-linking to attach or trap proteins to the microparticle's surface (Andrianov & Payne, 1998).